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Deuterated PZQ

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Was alerted to this NCTT project/proposal for deuterated analogs of enantiopure PZQ, with the deuteration being used to slow metabolism. Would be interesting to see how many D's are incorporated, and where (presumably at least the 4' position). I hope they're using our resolution approach to make their enantiopure material. And I wonder what the deuteration does to the cost, on scale?
(original page http://nctt.nih.gov/27545311)

Deuterated Analogs of Praziquantel for Treatment of Schistosomiasis

Program: Therapeutics for Rare and Neglected Diseases (TRND)

Key Investigators

CoNCERT Pharmaceuticals, Inc.Julie Fields Liu, Ph.D.

Abstract

Schistosomiasis (bilharzia) is caused by parasitic Schistosoma worms and is one of the Neglected Tropical Diseases in need of further research and treatment efforts. Schistosomiasis is second only to malaria as the most devastating parasitic disease, and more than 200 million people are infected worldwide in Africa, South America, the Caribbean, the Middle East, Southern China, and parts of Southeast Asia, Laos, and the Philippines. Humans contract the parasites following exposure to contaminated fresh water through bathing, wading, swimming, washing, etc. The parasites mature over several weeks and reside largely in the blood vessels, releasing eggs which can travel to the intestine, liver, or bladder and cause inflammation and scarring. Current standard of care for schistosomiasis is treatment with oral praziquantel (PZQ). It is well absorbed (80%) but is highly metabolized via a pronounced first-pass effect, resulting in low effective bioavailability. Over 99% of the dose is converted to oxidative metabolites via liver enzymes. As a result, in order to achieve therapeutic blood levels patients must be dosed repeatedly with multiple 600-mg tablets of PZQ at a level of 40-60 mg/kg over 1-2 days. According to the WHO, insufficient quantities of PZQ are available and less than 10% of the appropriate population receives treatment. PZQ is dosed as a racemate (50:50 mixture of R and S enantiomers) but only the R enantiomer contributes to the anti-parasitic efficacy. The extreme bitter taste of the drug can lead to vomiting, and attempts to mask the taste in a cost-effective manner have been unsuccessful. Interestingly, the bitter taste is more associated with the unneeded S enantiomer than with the active R enantiomer. CoNCERT Pharmaceuticals has synthesized deuterated analogs of PZQ and has demonstrated that selective deuterium incorporation imparts significant metabolic stabilization in vitro. These compounds are expected, based on CoNCERT's experience with numerous deuterium-modified drugs, to retain the positive pharmacologic effects of PZQ while potentially enabling lower doses and/or less frequent doses compared with the PZQ treatment regimen. Additionally, we have prepared R enantiomers of our analogs which may further facilitate smaller pill sizes, fewer pills per dose, and potentially a more palatable taste profile through the elimination of the unneeded S enantiomer. By metabolically stabilizing PZQ through deuterium substitution and selectively producing the R enantiomer, CoNCERT anticipates producing a significant improvement over the current standard of care. The first proof-of-concept milestone for the Deuterated Praziquantel project was achieved via the demonstration of metabolic stabilization in vitro for deuterated analogs versus PZQ. TRND will support preclinical studies and development activities leading up to a proof-of-concept Phase 1 trial in humans.

Keywords

Schistosomiasis; Praziquantel; PZQ; Deuterium

Public Health Impact

More than 200 million people are infected worldwide. Current standard of care for schistosomiasis involves multiple large doses of oral praziquantel (PZQ), which is highly metabolized resulting in low effective bioavailability. PZQ also has an extreme bitter taste which can cause vomiting and negatively impacts patient compliance with dosing. Insufficient quantities of PZQ are available and less than 10% of the appropriate population receives treatment. Deuterium-modified PZQ is expected to retain the positive pharmacologic effects of PZQ. Concert's early research suggests that deuterium-modified analogs of PZQ may require a substantially reduced effective dose. These analogs are also single enantiomers which may address the notably bitter taste and vomiting associated with PZQ, potentially resulting in improved tolerability.

Publications

Outcomes

Assessment of deuterium-based metabolic stabilization via in vitro and in vivo DMPK studies in multiple species to support lead candidate selection, followed by manufacturing campaigns and necessary preclinical studies to enable first-in-human dosing.

Project Details

This is one of the six TRND collaborations from TRND program's second solicitation.

It looks like these have come through, via Derwent/Thomson Pharma, from the ConCERT patent WO2010107791 that includes JFL as co-inventor. A quick scan suggests there is no reduction to practice so this was a prophetic filing, but you are duly cited (BTW patent citations can be picked up by Google Scholar). The structures are laid out on page 29 and include a di-flouro derivative that has been published. (http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=46885736&loc=ec_rcs). It might be prudent for ConCERT to explain the status of this application in context of the open efforts.